Growth regulation mediated by EGF family of growth factors

EGF 生长因子家族介导的生长调节

• 批准号: 14032202
• 负责人: MEKADA Eisuke
• 金额: $ 61.12万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research on Priority Areas
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14032202/
• 关键词: HB-EGF; EGF family; growth factor; ovarian cancer; diphtheria toxin; CRM197; 増殖因子; 膜結合型; 遺伝子ターゲッティング; 遺伝子欠損マウス; p38MAPK; 心不全

HB-EGF is a member of the EGF family growth factors. This factor is synthesized as proHB-EGF, a membrane-anchored precursor protein, and is cleaved on the cell surface to yield the soluble growth factor. The conversion of proHB-EGF into the soluble form is critical for the activity of this growth factor, and therefore this process is tightly regulated. We found that, among the EGFR family of growth factors, HB-EGF gene expression in cancerous tissues of ovarian cancer and HB-EGF protein levels in patients' ascites fluid were significantly elevated. The human ovarian cancer cell lines SKOV3 and RMG-1 form tumors in nude mice. Tumor formation of these cells was enhanced by exogenous expression of proHB-EGF, and completely blocked by proHB-EGF gene RNA interference or by CRM197, a specific HB-EGF inhibitor. Transfection with mutant forms of HB-EGF indicated that the release of soluble HB-EGF is essential for tumor formation. These results indicate that HB-EGF is the primary member of the EGFR family of growth factors expressed in ovarian cancer and that LPA-induced ectodomain shedding of this growth factor is a critical step in tumor formation, making HB-EGF a novel therapeutic target for ovarian cancer.

HB-EGF 是 EGF 家族生长因子的成员。该因子被合成为 proHB-EGF（一种膜锚定前体蛋白），并在细胞表面裂解产生可溶性生长因子。 proHB-EGF 转化为可溶形式对于该生长因子的活性至关重要，因此该过程受到严格监管。我们发现，EGFR生长因子家族中，卵巢癌癌组织中HB-EGF基因表达量和患者腹水中HB-EGF蛋白水平显着升高。人卵巢癌细胞系SKOV3和RMG-1在裸鼠体内形成肿瘤。 proHB-EGF 的外源表达增强了这些细胞的肿瘤形成，并被 proHB-EGF 基因 RNA 干扰或 CRM197（一种特异性 HB-EGF 抑制剂）完全阻断。用HB-EGF突变体转染表明可溶性HB-EGF的释放对于肿瘤形成至关重要。这些结果表明，HB-EGF是卵巢癌中表达的生长因子EGFR家族的主要成员，并且LPA诱导的该生长因子的胞外域脱落是肿瘤形成的关键步骤，使得HB-EGF成为卵巢癌的新治疗靶点。卵巢癌。

项目成果

Mice with defects in HB-EGF ectodomain shedding show severe developmental abnormalities.

• DOI: 10.1083/jcb.200307035
• 发表时间: 2003-11-10
• 期刊: JOURNAL OF CELL BIOLOGY
• 影响因子: 7.8
• 作者: Yamazaki, S;Iwamoto, R;Saeki, K;Asakura, M;Takashima, S;Yamazaki, A;Kimura, R;Mizushima, H;Moribe, H;Higashiyama, S;Endoh, M;Kaneda, Y;Takagi, S;Itami, S;Takeda, N;Yamada, G;Mekada, E
• 通讯作者: Mekada, E

Iwamoto, R., et al.: "HB-EGF and ErbB signaling is essential for heart function."Proc.Natl.Acad.Sci.U.S.A.. 100. 3221-3226 (2003)

Iwamoto, R. 等人：“HB-EGF 和 ErbB 信号传导对于心脏功能至关重要。”Proc.Natl.Acad.Sci.U.S.A.. 100. 3221-3226 (2003)

Ligand-independent dimer formation of EGFR is a step separable from ligand-induced EGFR signaling.

EGFR 的配体独立二聚体形成是与配体诱导的 EGFR 信号传导分开的一个步骤。

• 发表时间: 2002
• 期刊: Mol. Biol. Cell 13
• 作者: Yu;X.;et al.
• 通讯作者: et al.

Takeda, Y., et al.: "Tetraspanins CD9 and CD81 function to prevent the fusion of mononuclear phagocytes."J.Cell Biol.. 161. 945-956 (2003)

Takeda, Y., et al.：“四跨膜蛋白 CD9 和 CD81 的功能是防止单核吞噬细胞的融合。”J.Cell Biol.. 161. 945-956 (2003)

Suppression of the biological activities of the EGF-like domain by the heparin-binding domain of heparin-binding EGF-like growth factor.

肝素结合 EGF 样生长因子的肝素结合结构域对 EGF 样结构域的生物活性的抑制。

• 发表时间: 2004
• 期刊: J.Biol.Chem. 279・45
• 作者: Takazaki;R.他3名
• 通讯作者: R.他3名